Tuberculosis causes nearly two million deaths annually. Recent years have witnessed a resurgence of efforts directed at tuberculosis (TB) drug research and development. An analysis of the chronology of anti-tuberculosis therapy suggests a renewed interest in tuberculosis research. Since the 1960s and 70s same generation of antibiotics or their derivatives are being used against Mycobacterium tuberculosis even though there is resistance against the drugs with the development of drug resistant strains such as Multidrug resistance TB (MDR-TB) which are resistant to at least isoniazid (INH) and rifampicin (RMP), the two most powerful first-line treatment anti-TB drugs; extensively drug resistance TB (XDR-TB) which are resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs such as amikacin, kanamycin, or capreomycin and totally drug resistance TB (TDR-TB) which are resistant to all first and second line drugs tested such as isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, ethionamide, para-aminosalicylic acid, cycloserine, ofloxacin, amikacin, ciprofloxacin, capreomycin, kanamycin.
India has the world's one of the highest burden of tuberculosis, wherein MDR tuberculosis accounts for nearly 5 lakhs cases annually which have been increased by more than 6% in the past 10 years.
It is said that M. tuberculosis develops resistance to drugs by induced or spontaneous mutation of its genome. It is also hypothesized that in case of certain drugs the bacterial cell wall, does not permit adequate permeability, thereby resulting in inadequate/minor amount of drug entering the bacteria. Such amount is insufficient to kill the bacteria, but the presence of minor amount, induces the bacteria to become resistant to the same. It is also hypothesized that M. tuberculosis acquires resistance by modification of its enzyme by unknown mechanisms. Traditional antitubercular drugs administered via oral route, act by inhibiting the synthesis of mycolic acid and/or by inhibiting the mycobacterial arabinosyltransferase, an essential component of mycobacterial cell wall. Few systemic antitubercular drugs also act by crossing the lipid bilayer and bind to one of the ribosome sub-unit, inhibiting the protein synthesis. Based on mechanism of action of these drugs, these drugs have a high probability of inducing mutation and/or have problems of permeability, increasing the chances of drug resistant strains.
G-protein coupled receptors such as GPR109A also plays an important role in tuberculosis. GPR109A receptor is located on the cell surface and inhibits adenylyl cyclase along with consequent suppression of PKA-signaling resulting in reduced triglyceride turnover which is further responsible for accumulation of lipid body inside the cell. Increase in the concentration of lipid body inside the cell favors the growth of M. tuberculosis and prevents respiratory burst. A GPR109A inhibitor prevents the formation of lipid body by creating a hostile environment for the tuberculosis and thus induces respiratory burst. Host macrophages infected by M. tuberculosis acquire foamy phenotype characterized by the intracellular accumulation of lipid bodies induced by pathogen through modulation of lipolysis of neutral lipids. This dysregulation influences the lipolysis by modulating the cAMP dependent signaling pathway.
Current resistant tuberculosis treatment, has greater risk of side effects and lasts for 18-24 months and target processes or enzymes within M. tuberculosis but suffers from the risk of generating newer variants exhibiting drug resistance. Since, M. tuberculosis survives within the human macrophage through modulation of a range of host cellular processes hence, a pharmacological target within the host that has been co-opted by M. tuberculosis for its survival should be a breakthrough approach for therapy. Additionally such an approach should be insensitive to whether the infecting strain was drug sensitive or drug resistant and preclude the development of resistance.